Cardiovascular disease associated with atherosclerosis takes an enormous toll on human life and is responsible for a major portion of health care costs in the U.S. Although the advent of statin therapies has reduced the risk of mortality from coronary heart disease through both cholesterol-lowering and immunomodulatory effects, heart disease remains a major cause of death in this country. Thus, there is a critical need for new interventions capable of altering the underlying biochemical and cellular events that promote atherosclerosis. Recombinant interferon-beta (IFN-beta) is an approved immunomodulatory drug with an excellent safety record that has been used to safely treat thousands of patients with multiple sclerosis (MS). Based on its purported mechanisms of action in the treatment of multiple sclerosis (MS), IFN-beta appears to have promise as an anti-atherosclerotic agent. In preliminary studies, recombinant IFN-beta was shown to reduce aortic lesion size and inflammation in a mouse model of atherosclerosis. However, the high cost, frequent side effects, and inconvenient administration schedule associated with recombinant IFN-beta protein therapy is likely to preclude its widespread use in the cardiovascular disease setting. In order to realize the potential benefits of IFN-beta therapy in atherosclerosis, this proposal will evaluate an alternative method of delivery based on electroporation (EP)-mediated intramuscular transfer of plasmid DNA encoding the IFN-beta gene. The basic feasibility of the proposed DNA-based IFN-beta product as a treatment for atherosclerosis is dependent on demonstrating that gene-based IFN-beta delivery is capable of reducing the severity of atherosclerosis. Thus, the first aim of these studies will evaluate the ability of EP-mediated gene-based IFN-beta therapy to attenuate plaque formation in a well characterized mouse model of atherosclerosis. For a successful product, it will be necessary to demonstrate that the combination of gene-based IFN-beta and conventional statin therapy are superior to statin therapy alone; this will be addressed in the second Aim. Additionally, these studies will characterize any adverse events associated with gene-based IFN-beta administration, either alone or in combination with statin therapy. If efficacy and initial safety studies indicate that a gene-based IFN-beta therapy for atherosclerosis is feasible, further non-clinical testing will be completed and a Phase I human clinical study will be initiated in SBIR Phase II. [unreadable] [unreadable] Atherosclerosis is a chronic inflammatory process that occurs within the cardiovascular system and leads to a thickening of artery walls and the formation of plaques that restrict blood flow. Atherosclerosis is linked to nearly 75% of all deaths from cardiovascular diseases, and there is a great need for new therapies that will slow its progression. The proposed studies will evaluate the potential of a gene-based interferon-beta therapy for atherosclerosis, and thus will address a very critical need in current medical care. [unreadable] [unreadable] [unreadable]